The Open Virology Journal




ISSN: 1874-3579 ― Volume 13, 2019
REVIEW ARTICLE

Hepatitis C Virus and Hepatocellular Carcinoma: Pathogenetic Mechanisms and Impact of Direct-Acting Antivirals



Ivan Schietroma1, Giuseppe Corano Scheri1, *, Claudia Pinacchio1, Maura Statzu2, Arnolfo Petruzziello3, Vincenzo Vullo1
1 Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Rome, Italy
2 Department of Molecular Medicine, Laboratory of Virology, “Sapienza” University of Rome, Rome, Italy
3 Virology and Molecular Biology Unit, Department of Diagnostic Pathology, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy

Abstract

Introduction:

Globally, between 64 and 103 million people are chronically infected with Hepatitis C virus (HCV), with more than 4.6 million people in the United States and is associated with more than 15.000 deaths annually. Chronic infection can result in cirrhosis and hepatocellular carcinoma.

Explanation:

Epidemiological studies have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC), mainly through chronic inflammation, cell deaths, and proliferation. Despite the new direct-acting antiviral drugs (DAA’s) being able to clear the HCV, HCC recurrence rate in these patients is still observed.

Conclusion:

In this review we highlighted some aspects that could be involved in the onset of HCV-induced HCC such as immune system, viral factors and host genetics factors.

Moreover, we focused on some of the last reports about the effects of DAA’s on the HCV clearance and their potential implications in HCC recurrence.

Keywords: HCV, HCC, DAA’s, Immunity, Viral factors, Chronic infection.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
Issue: Suppl-1, M2
First Page: 16
Last Page: 25
Publisher Id: TOVJ-12-16
DOI: 10.2174/1874357901812010016

Article History:

Received Date: 28/08/2017
Revision Received Date: 26/09/2017
Acceptance Date: 02/02/2018
Electronic publication date: 28/02/2018
Collection year: 2018

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© 2018 Schietroma et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Rome, Italy; Tel: +393896943773; E-mail: giuseppe.coranoscheri@uniroma1.it




1. INTRODUCTION

Hepatocellular carcinoma (HCC), also known as malignant hepatoma, is a primary malignant tumor of the liver arising from the liver cells (hepatocytes) [1Chacko S, Samanta S. “Hepatocellular carcinoma: A life-threatening disease”. Biomed Pharmacother 2016; 84: 1679-88.[http://dx.doi.org/10.1016/j.biopha.2016.10.078] [PMID: 27823920] ].

Amongst the most common tumors worldwide [2Elia G, Fallahi P. Hepatocellular carcinoma and CXCR3 chemokines: A narrative review. Clin Ter 2017; 168(1): e37-41.[PMID: 28240761] ], it occurs predominantly in patients with underlying chronic liver disease and cirrhosis.

In the United States, HCC is the ninth leading cause of cancer deaths [3Balogh J, Victor D III, Asham EH, et al. Hepatocellular carcinoma: A review. J Hepatocell Carcinoma 2016; 3: 41-53.[http://dx.doi.org/10.2147/JHC.S61146] [PMID: 27785449] ]. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise (662,000 deaths worldwide per year) [2Elia G, Fallahi P. Hepatocellular carcinoma and CXCR3 chemokines: A narrative review. Clin Ter 2017; 168(1): e37-41.[PMID: 28240761] ].

HCC occurs more often in males than females (ratio 2,4:1) and it is common between the age of 30 to 50 [2Elia G, Fallahi P. Hepatocellular carcinoma and CXCR3 chemokines: A narrative review. Clin Ter 2017; 168(1): e37-41.[PMID: 28240761] ], peaking at approximately 70 years of age and with a higher incidence in Eastern and Southern Asia, Middle and Western Africa, Melanesia, and Micronesia/Polynesia [3Balogh J, Victor D III, Asham EH, et al. Hepatocellular carcinoma: A review. J Hepatocell Carcinoma 2016; 3: 41-53.[http://dx.doi.org/10.2147/JHC.S61146] [PMID: 27785449] ].

1.1. Risk Factors

The distribution of risk factors in patients with HCC depends on the ethnic group, race or geographical region. The most common risk factors are: infection with Hepatitis B virus (HBV) or Hepatitis C virus (HCV), alcoholic liver diseases, Non-Alcoholic Fatty Liver (NAFLD), Non-Alcoholic Steatohepatitis (NASH) and aflatoxins [1Chacko S, Samanta S. “Hepatocellular carcinoma: A life-threatening disease”. Biomed Pharmacother 2016; 84: 1679-88.[http://dx.doi.org/10.1016/j.biopha.2016.10.078] [PMID: 27823920] ]. Less common causes include sex and metabolic and genetic diseases such as diabetes mellitus, obesity, hemochromatosis and Wilson’s disease.

The above-mentioned risk factors often lead to the formation and progression of cirrhosis, which is present in 80 to 90% of patients with hepatocellular carcinoma.

In the developing world, viral hepatitis (primarily hepatitis B) continues to represent a major risk for the development of HCC. Worldwide, chronic HBV infection accounts for approximately 50% of all cases of hepatocellular carcinoma and virtually all childhood cases.

The World Health Organization estimates that every year 3–4 million people get infected with hepatitis C virus (HCV) worldwide. Whereas 130–170 millions of chronically infected individuals are at risk of developing liver Cirrhosis, Hepatocellular Carcinoma (HCC), or both. These infections induce over 350 thousand deaths per annum, but the manifestation varies widely with geographical deviations. The prevalence is as low as 0.1–1% in northern Europe to 2.5–3.5% in southern Europe. Amongst the most affected countries is Egypt, with 22% of its population infected, followed by Pakistan and China, with more than 3% of their population infected with HCV [4Nawaz R, Zahid S, Idrees M, et al. HCV-induced regulatory alterations of IL-1β, IL-6, TNF-α, and IFN-ϒ operative, leading liver en-route to non-alcoholic steatohepatitis. Inflamm Res 2017; 66(6): 477-86.[http://dx.doi.org/10.1007/s00011-017-1029-3] [PMID: 28285394] ].

Hepatitis C virus infection was first suspected in the 1970s, when most blood transfusion infections were associated with either hepatitis A or hepatitis B virus. This new type of blood-transmitted hepatitis was then called “non-A, non-B” hepatitis.

The genome of HCV was identified in 1989, and the name hepatitis C was subsequently applied to human infection caused by this single-strand Ribonucleic Acid (RNA) virus of positive polarity [5de Oliveria Andrade LJ, D’Oliveira A, Melo RC, De Souza EC, Costa Silva CA, Paraná R. Association between hepatitis C and hepatocellular carcinoma. J Glob Infect Dis 2009; 1(1): 33-7.[http://dx.doi.org/10.4103/0974-777X.52979] [PMID: 20300384] ].

Although its origin remains unclear, HCV might have originated from zoonotic sources such as non-human primates (e.g. monkeys, apes) and mammals (e.g. dogs, horses) [6Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res 2017; 142: 83-122.[http://dx.doi.org/10.1016/j.antiviral.2017.02.014] [PMID: 28238877] ].

Hepatitis C virus belongs to the Hepacivirus genus, Flaviviridae family, and exhibits high genetic variability. There are seven different genotypes, and more than 70 subtypes [5de Oliveria Andrade LJ, D’Oliveira A, Melo RC, De Souza EC, Costa Silva CA, Paraná R. Association between hepatitis C and hepatocellular carcinoma. J Glob Infect Dis 2009; 1(1): 33-7.[http://dx.doi.org/10.4103/0974-777X.52979] [PMID: 20300384] ] and their global prevalence is unequally distributed. Amongst 7 HCV genotypes, genotype 1 and 3 account respectively for 46.2 and 30.1% of the global infections; genotypes 2, 4, and 6 are present in approximately 22.8% of HCV infections and genotype 5 represents the remaining less than 1%; genotype 7 has been identified so far in very few patients originating from Central Africa [6Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res 2017; 142: 83-122.[http://dx.doi.org/10.1016/j.antiviral.2017.02.014] [PMID: 28238877] ].

A single HCV particle is approximately 68 nm in diameter [6Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res 2017; 142: 83-122.[http://dx.doi.org/10.1016/j.antiviral.2017.02.014] [PMID: 28238877] ].

A lipid bilayer envelope surrounds a capsid. The viral envelope bears E1 and E2 glycoprotein complex that plays a fundamental role in viral and host cell interaction [4Nawaz R, Zahid S, Idrees M, et al. HCV-induced regulatory alterations of IL-1β, IL-6, TNF-α, and IFN-ϒ operative, leading liver en-route to non-alcoholic steatohepatitis. Inflamm Res 2017; 66(6): 477-86.[http://dx.doi.org/10.1007/s00011-017-1029-3] [PMID: 28285394] ].

Viral genome, comprised of 9600 nucleotides, encodes a 3000 aminoacid polyprotein, which is post-translationally modified into three structural proteins and six non-structural proteins. Structural proteins, Core, E1, and E2, create the capsid and the envelope, while non-structural proteins, NS2, NS3, NS4A, NS4B, NS5A, and NS5B, are the building blocks for the particle and play a vital role as genome replicating proteins [4Nawaz R, Zahid S, Idrees M, et al. HCV-induced regulatory alterations of IL-1β, IL-6, TNF-α, and IFN-ϒ operative, leading liver en-route to non-alcoholic steatohepatitis. Inflamm Res 2017; 66(6): 477-86.[http://dx.doi.org/10.1007/s00011-017-1029-3] [PMID: 28285394] ].

Alcohol abuse is an important risk factor for development accounting for 40%–50% of all HCC cases in Europe. The relationship between alcohol and liver disease correlates with the amount of alcohol consumed over a lifetime, with heavy alcohol use rather than social drinking being the main risk of HCC.

Chronic diseases such as diabetes mellitus and obesity increase the risk of HCC. Diabetes mellitus directly affects the liver because of the essential role the liver plays in glucose metabolism.

Hyperinsulinemia has been associated with a threefold increased risk of HCC. It is believed that the pleotropic effects of insulin which regulate the anti-inflammatory cascade and other pathways inducing cellular proliferation, play a role in carcinogenesis.

It is well established that obesity is associated with many hepatobiliary diseases, including nonalcoholic fatty liver disease (NAFLD), steatosis, and cryptogenic cirrhosis, all of which can lead to HCC.

Gender may also play a role in the development (growth, evolution, production) of Hepatoma, occurring more often in males, with a ratio of 2:1– 4:1 . Males are more likely to get infected with viral hepatitis, consume greater quantities of alcohol, smoke cigarettes, and have a higher body mass index than women. Higher testosterone levels may also increase the incidence in males and the formation of liver adenomas.

Aflatoxins, metabolites of the fungi Aspergillus flavus and Aspergillus parasiticus are frequent contaminants of food, and are associated with a high rate of HCC development [7Kew MC. Aflatoxins as a cause of hepatocellular carcinoma. J Gastrointestin Liver Dis 2013; 22(3): 305-10.[PMID: 24078988] ]. The risk of HCC with aflatoxin depends on the amount and duration of exposure. Aflatoxin exerts a synergistic effect on hepatitis B- and C-induced liver cancer, with the risk being 30 times greater with chronic hepatitis B plus aflatoxin exposure than with aflatoxin exposure alone [3Balogh J, Victor D III, Asham EH, et al. Hepatocellular carcinoma: A review. J Hepatocell Carcinoma 2016; 3: 41-53.[http://dx.doi.org/10.2147/JHC.S61146] [PMID: 27785449] , 8Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: A risk assessment. Environ Health Perspect 2010; 118(6): 818-24.[http://dx.doi.org/10.1289/ehp.0901388] [PMID: 20172840] ].

Metabolic and genetic diseases associated with HCC include hemochromatosis, Wilson’s disease, alfa-1 antitrypsin disease, tyrosinemia, glycogen-storage disease types I and II, and porphyrias. Other risk factors may include cigarette smoke, associated with a significant increase in the development of HCC [3Balogh J, Victor D III, Asham EH, et al. Hepatocellular carcinoma: A review. J Hepatocell Carcinoma 2016; 3: 41-53.[http://dx.doi.org/10.2147/JHC.S61146] [PMID: 27785449] ].

1.2. Pathogenesis

As a blood-borne virus, HCV can be transmitted over blood transfusions, needle sharing, sexual contacts, or maternal transmission. Although HCV can circulate in many human organs, it especially infects hepatocytes in the liver and evades the host innate and adaptive immune system. With an incubation period of 2 to 12 weeks, HCV infection begins with an acute phase that usually goes undiagnosed, during which symptomatic infections (10% to 15%) and asymptomatic infections (85% to 90%) are observed. Approximately, 25% to 52% of symptomatic infections and 10% to 15% of asymptomatic infections undertake spontaneous viral clearance, indicating that HCV is cleared from HCV-infected patients by specific immune responses. If not cleared, acute HCV evolves into chronic HCV. Without proper treatment, patients with chronic HCV are threatened by serious complications such as cirrhosis, liver cancer, and liver failure. Liver damage is a consequence of long-lasting inflammation when host immune responses are activated to fight HCV infections [6Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res 2017; 142: 83-122.[http://dx.doi.org/10.1016/j.antiviral.2017.02.014] [PMID: 28238877] ].

Hepatocarcinogenesis is a highly complex multistep process: it starts from hepatic stem cells or mature hepatocytes under the condition of chronic liver disease initiated by oxidative stress, chronic inflammation and cell death followed by uncontrolled proliferation/restricted regeneration and permanent liver remodeling.

In response to cytokine stimulation caused by hepatocyte injury, extensive compensatory cell proliferation and regeneration take place, followed by fibrosis and cirrhosis, particularly driven by the synthesis of extracellular matrix components from hepatic stellate cells. Finally, in this carcinogenic environment, hyperplastic and dysplastic nodules form and normal liver tissue turns cancerous. The molecular pathogenesis of HCC involves different genetic/epigenetic aberrations and alterations in multiple signaling pathways leading to the known heterogeneity of the disease concerning its biologic and clinical behavior [1Chacko S, Samanta S. “Hepatocellular carcinoma: A life-threatening disease”. Biomed Pharmacother 2016; 84: 1679-88.[http://dx.doi.org/10.1016/j.biopha.2016.10.078] [PMID: 27823920] ].

2. IMMUNITY

In patients persistently infected with HCV, chronic inflammation resulting from the immune response against infected hepatocytes typically lasts many decades and it frequently leads to progressive liver disease that ranges from inflammation to severe fibrosis, that can culminate in hepatic cirrhosis and Hepatocellular Carcinoma (HCC) [9Vegna S, Gregoire D, Moreau M, et al. NOD1 participates in the innate immune response triggered by Hepatitis C virus polymerase. J Virol 2016; 90(13): 6022-35.[http://dx.doi.org/10.1128/JVI.03230-15] [PMID: 27099311] ].

A variety of PRRs (Pattern Recognition Receptors) sense viruses as foreign invaders within the host cell through specific PAMP (Pathogen Associated Molecular Patterns) recognition to activate innate immune signalling [10Horner SM, Gale M Jr. Regulation of hepatic innate immunity by hepatitis C virus. Nat Med 2013; 19(7): 879-88.[http://dx.doi.org/10.1038/nm.3253] [PMID: 23836238] ]. The 3 major classes of PRRs include Toll-like receptors (TLRs), RIG-1-like receptors (RLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs) [11Buonaguro L, Petrizzo A, Tornesello ML, Buonaguro FM. Innate immunity and hepatitis C virus infection: A microarray’s view. Infect Agent Cancer 2012; 7(1): 7.[http://dx.doi.org/10.1186/1750-9378-7-7] [PMID: 22448617] ].

NS5B, the HCV RNA-dependent polymerase, can activate innate immune signalling through dsRNAs that are transcribed from nonspecific cellular templates. Both TLR3 and RIG-1 can trigger cellular responses to RNA produced by NS5B, but Vegna et al. showed that NS5B induces and activates NOD1, a receptor classically associated with a response to bacterial infection, that has as downstream effector RIPK2, which leads to MAPK activation, type I interferon production and NF-κB-dependent signalling [9Vegna S, Gregoire D, Moreau M, et al. NOD1 participates in the innate immune response triggered by Hepatitis C virus polymerase. J Virol 2016; 90(13): 6022-35.[http://dx.doi.org/10.1128/JVI.03230-15] [PMID: 27099311] ]. The persistent inflammatory response observed in the liver of HCV-positive patients thus impacts many aspects of HCV-associated pathology, including HCC, by creating a favorable environment for disease progression [9Vegna S, Gregoire D, Moreau M, et al. NOD1 participates in the innate immune response triggered by Hepatitis C virus polymerase. J Virol 2016; 90(13): 6022-35.[http://dx.doi.org/10.1128/JVI.03230-15] [PMID: 27099311] ].

Recently, Lopes et al. [12Lopes JA, Borges-Canha M, Pimentel-Nunes P. Innate immunity and hepatocarcinoma: Can toll-like receptors open the door to oncogenesis? World J Hepatol 2016; 8(3): 162-82.[http://dx.doi.org/10.4254/wjh.v8.i3.162] [PMID: 26839640] ] have shown that TLRs are closely related to carcinogenesis. Also myeloid differentiation factor 88 (MyD88), the TLR and interleukin (IL)-1 receptor adaptor molecule, has been linked to tumorigenesis. Kinowaki et al. [13Kinowaki K, Soejima Y, Kumagai A, et al. Clinical and pathological significance of myeloid differentiation factor 88 expression in human hepatocellular carcinoma tissues. Pathol Int 2017; 67(5): 256-63.[http://dx.doi.org/10.1111/pin.12529] [PMID: 28370778] ] examined the expression of MyD88 in human HCC tissues, finding that attenuated expression of MyD88 in HCC tissues is associated with tumor progression. This was in contrast with other recent reports [14Liang B, Chen R, Wang T, et al. Myeloid differentiation factor 88 promotes growth and metastasis of human hepatocellular carcinoma. Clin Cancer Res 2013; 19(11): 2905-16.[http://dx.doi.org/10.1158/1078-0432.CCR-12-1245] [PMID: 23549880] -16Wang EL, Qian ZR, Nakasono M, et al. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. Br J Cancer 2010; 102(5): 908-15.[http://dx.doi.org/10.1038/sj.bjc.6605558] [PMID: 20145615] ].

Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) is a newly identified protein essential for the maintenance of immune homeostasis and for tumorigenesis suppression. Recently, a study showed that another HCV protein, NS5B, can lead to hepatocellular carcinogenesis by promoting TIPE2 degradation [17Wang Y, Jiang Y, Zhou J, et al. Hepatitis C virus promotes hepatocellular carcinogenesis by targeting TIPE2, a new regulator of DNA damage response. Tumour Biol 2016; 37(11): 15265-74.[http://dx.doi.org/10.1007/s13277-016-5409-z] [PMID: 27696294] ].

Golgi protein 73 (GP73) is a serum biomarker for liver disease and HCC with high specificity and sensitivity. However, the mechanism underlying GP73 regulating HCV infection is poorly understood. Zhang et al. [18Zhang X, Zhu C, Wang T, et al. GP73 represses host innate immune response to promote virus replication by facilitating MAVS and TRAF6 degradation. PLoS Pathog 2017; 13(4): e1006321.[http://dx.doi.org/10.1371/journal.ppat.1006321] [PMID: 28394926] ] discovered that GP73 acts as a negative regulator of host innate immunity: it binds directly to mitochondrial antiviral signaling protein (MAVS) and TNF receptor-associated factor 6 (TRAF6) to promote their degradation, which result in the repression of host innate immunity and facilitation of HCV infection.

Persistent infection by hepatitis C virus (HCV) represents one of the main risk factors for HCC and has been shown to impair NK-cell response, mainly exerting a suppressive function that might play a role in tumor promotion or progression [19Cariani E, Pilli M, Barili V, et al. Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments. OncoImmunology 2016; 5(8): e1154249.[http://dx.doi.org/10.1080/2162402X.2016.1154249] [PMID: 27622055] ].

With the aim to investigate the phenotype and function of peripheral blood NK in HCV-linked HCC and their possible prognostic implications, Cariani et al. [19Cariani E, Pilli M, Barili V, et al. Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments. OncoImmunology 2016; 5(8): e1154249.[http://dx.doi.org/10.1080/2162402X.2016.1154249] [PMID: 27622055] ] evaluated a cohort of patients with HCV-related HCC: they found a decreased expression of inhibitory receptor NKG2A and of molecules linked to effector function (CD3z, perforin) in peripheral blood NK-cells from HCC patients. The study thus supports prognostic relevance of NK-cell phenotype and function in HCC.

3. HCV AND HCC: WHAT ABOUT GENETICS?

There are 3 IFN-lambda genes that encode 3 distinct but highly related proteins denoted as IFN-lambda1, -lambda2, and -lambda3. These proteins are also known as interleukin-29 (IL-29), IL-28A, and IL-28B, respectively. Only recently IFN lambda 4, a new member of the family, was discovered. These cytokines comprise the type III subset of IFNs [20Donnelly RP, Kotenko SV. Interferon-lambda: A new addition to an old family. J Interferon Cytokine Res 2010; 30(8): 555-64.[http://dx.doi.org/10.1089/jir.2010.0078] [PMID: 20712453] ]. In HCV infected patients, genetic variations in the IFNλ locus are associated with spontaneous viral clearance and type I IFN-based treatment success [21Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009; 461(7265): 798-801.[http://dx.doi.org/10.1038/nature08463] [PMID: 19759533] , 22Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461(7262): 399-401.[http://dx.doi.org/10.1038/nature08309] [PMID: 19684573] ]. Three major SNP near IFNL3 and INFL4 genes correlate with HCV treatment response: rs12979860(C/T), rs8099917(T/G) and rs368234815(TT/ΔG) [23Bruening J, Weigel B, Gerold G. The role of type III interferons in Hepatitis C virus infection and therapy J Immunol Res 2017.]. The molecular mechanisms that control the association between IFNλ polymorphisms and the clinical outcome of HCV infection still remain unclear.

In 2015, a study demonstrated a correlation between the rs8099917 SNP and IL28B serum levels, while other SNPs, including rs12979860 failed to show a similar correlation. They observed that the T-allele of rs8099917 was correlated with reduced IL28B serum levels. Also, they found that IL28B serum levels had significant correlation with the different outcomes of HCV infection, especially among patients suffering from cirrhosis and HCC, where IL28 serum level tend to increase with the progression of the disease, but even if IL28B variants might play a significant role in HCV infection, they may not be considered as risk factors in the progression of the infection to advanced stages such as HCC. However, further investigations are needed to explain the effect of IL28B levels on disease progression [24Al-Qahtani A, Al-Anazi M, Abdo AA, et al. Correlation between genetic variations and serum level of interleukin 28B with virus genotypes and disease progression in chronic hepatitis C virus infection. J Immunol Res 2015.].

TLRs are a group of molecules that are essential for the innate immune response against pathogens. De Re et al. in 2016 investigated the hypothesis of a functional connection between IL28B and toll-like receptor 2, a pattern recognition receptor that has specific polymorphism associated with hepatocarcinogenesis. This study emphasizes that both TLR2 and IL28B polymorphism may have a role in directing HCV-progression towards hepatic diseases: in particular, the presence of IL28B-C allele in homozygosity has a potential protective effect towards chronic infection and liver diseases, but the simultaneous presence of at least one TLR2-del allele abolished this effect; the TLR2-del/del state appeared also closely linked with HCC condition [25De Re V, De Zorzi M, Caggiari L, et al. HCV-related liver and lymphoproliferative diseases: Association with polymorphisms of IL28B and TLR2. Oncotarget 2016; 7(25): 37487-97.[http://dx.doi.org/10.18632/oncotarget.9303] [PMID: 27183918] ].

Lately, Yuan et al. described the TLR3 mediated antitumor activities towards HCC. In 2017 a study of Al-Anazi investigated the influence of genetic variants within TLR3 with the purpose to determine the association with HCV infection and HCV-related liver damage that results in cirrhosis and HCC. They found that rs78726532 was strongly associated with HCV infection. Moreover, the rs78726532 GG genotype had a protective role for HCV infection. Three more TLR3 SNPs were associated with HCV related end stage liver disease progression (liver cirrhosis and HCC) [26Al-Anazi MR, Matou-Nasri S, Abdo AA, et al. Association of toll-like receptor 3 single-nucleotide polymorphisms and hepatitis C virus infection. J Immunol Res 2017.].

In 2014, Mc Farland et al. reported the identification of a functional polymorphism (rs4803217) located in the 3′ untranslated region (3′ UTR) of the IFNL3 mRNA that dictates transcript stability. This polymorphism influences AU-rich element-mediated decay as well as the binding of HCV-induced microRNAs during infection. Together, these pathways mediate robust repression of the unfavorable IFNL3 genotype [27McFarland AP, Horner SM, Jarret A, et al. The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs. Nat Immunol 2014; 15(1): 72-9.[http://dx.doi.org/10.1038/ni.2758] [PMID: 24241692] ]. More recently, another study compared rs4803217 to IFNL4-ΔG/TT, a functional variant that controls generation of the IFNL4 protein, showing evidence that the IFNL4- ΔG allele is a primary variant for impaired clearance of HCV [28O’Brien TR, Pfeiffer RM, Paquin A, et al. Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance. J Hepatol 2015; 63(5): 1103-10.[http://dx.doi.org/10.1016/j.jhep.2015.06.035] [PMID: 26186989] ].

Another study has recently shown the association between SNPs in 3 genes involved in early immune response against HCV and the risk of progressive liver disease: low molecular mass polypeptide 7 (LMP-7), interleukin 28B (IL28B) and 2’-5’oligoadenylate synthetase 1 (OAS1). In particular, SNPs in LMP-7 and IL28B rs12979860 are associated with the development of HCC [29Ibrahim MK, Salama H, Abd El Rahman M, et al. Three gene signature for predicting the development of hepatocellular carcinoma in chronically infected hepatitis C virus patients. J Interferon Cytokine Res 2016; 36(12): 698-705.[http://dx.doi.org/10.1089/jir.2016.0042] [PMID: 27726464] ].

These findings highlight the importance of host genetic factors in determining the early stages of HCV infection and the development of HCV-associated HCV diseases.

4. VIRAL AND NON-VIRAL FACTORS INVOLVED IN HCV-RELATED HCC

The escape from the immune system may represent one of the mechanisms by which HCV establishes persistent infection and which contributes to the maintenance and development of cancer. Epidemiological studies on the association between hepatitis C virus infection and Hepatocellular carcinoma (HCC) development have begun in rapid succession after the development of the first detection test specific antibody [30Bukh J. The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control. J Hepatol 2016; 65(1)(Suppl.): S2-S21.[http://dx.doi.org/10.1016/j.jhep.2016.07.035] [PMID: 27641985] ]. A direct role in inducing HCC was highlighted in transgenic mice for core expression in which the induction of hepatic carcinoma is accelerated [31Chevaliez S, Pawlotsky J-M. HCV genome and life cycle.hepatitis C viruses: Genomes and molecular biology [Internet]2006. [cited 2017 May 11]http://www.ncbi.nlm.nih.gov/books/NBK1630/]. Direct and indirect pathways of carcinogenesis are responsible for HCC development and understanding of these pathways will be key to devising new treatment strategies. The most important mechanisms are: direct pathways involving the HCV core protein, indirect injury from oxidative stress and steatosis leading to hepatocyte death, and micro RNA (mi-RNA) instability. The possible mechanisms for HCC induction by the HCV virus are, however, little known being an RNA virus in which the replicative cycle, which occurs in the cytoplasm, a DNA phase is not present or the possibility of viral integrals or viral oncogenes is known [32Selimovic D, El-Khattouti A, Ghozlan H, Haikel Y, Abdelkader O, Hassan M. Hepatitis C virus-related hepatocellular carcinoma: An insight into molecular mechanisms and therapeutic strategies. World J Hepatol 2012; 4(12): 342-55.[http://dx.doi.org/10.4254/wjh.v4.i12.342] [PMID: 23355912] ]. It is believed that an important role is given by viral persistence in immune stimulus incessant exercise. Consequently, the HCV core protein plays a pivotal role in the development of direct mechanisms of HCC; in fact, the core deregulates the pathways by inhibiting retinoblastoma protein (RB) and p53 tumor suppressor [33Conti B, Porcu C, Viscomi C, et al. Small heterodimer partner 1 directly interacts with NS5A viral protein and has a key role in HCV related liver cell transformation. Oncotarget 2016; 7(51): 84575-86.[http://dx.doi.org/10.18632/oncotarget.12144] [PMID: 27661118] ]. Furthermore, HCV NS5 inhibits the apoptosis regulators BCL-2, and it is the cause of abnormal activation of signaling pathways that promote growth, such as Wnt/beta catenin and mammalian target of rapamycin (mTOR) [34He L, Tian D-A, Li P-Y, He X-X. Mouse models of liver cancer: Progress and recommendations. Oncotarget 2015; 6(27): 23306-22.[http://dx.doi.org/10.18632/oncotarget.4202] [PMID: 26259234] ]. Further, hypotheses are related to a possible indirect role of some viral proteins, in particular core protein and NS5. HCV core protein interacts with different routes of intracellular signal transduction (TNF-α, NF-kB, activation of the path induced by oxidative stress: kinase MAPK, JNK / SAPK); inhibits and induces apoptosis Fas- and TNF-α mediated thus contributing to increased survival or increased proliferation of hepatocytes [35Maass T, Sfakianakis I, Staib F, Krupp M, Galle PR, Teufel A. Microarray-based gene expression analysis of hepatocellular carcinoma. Curr Genomics 2010; 11(4): 261-8.[http://dx.doi.org/10.2174/138920210791233063] [PMID: 21119890] ]. The research group of Dr. Conti highlighted, during HCV life cycle with the help of a HCV infection model, a functional interaction between Small Heterodimer Protein 1 (SHP1), a steatogenic protein, and HCV NS5A protein. They demonstrated that SHP1 silencing (siSHP1) reversed the pro-oncogenic effects of HCV infection, inducing a significant decrease in liver lipid accumulation and in NS5A protein expression. Moreover, siSHP1 causes a strong modulation of some genes involved in HCV-related EMT, such as: HNF4, a central regulators of hepatocyte differentiation, E-Cadherin, SNAILs. This data suggest that SHP1 has been shown not only to be strictly connected to the pathogenesis of HCV-related liver steatosis, but also to its progression towards liver transformation [36Kannan RP, Hensley LL, Evers LE, Lemon SM, McGivern DR. Hepatitis C virus infection causes cell cycle arrest at the level of initiation of mitosis. J Virol 2011; 85(16): 7989-8001.[http://dx.doi.org/10.1128/JVI.00280-11] [PMID: 21680513] ]. HCC microarray analysis suggested that some clusters of genes involved in growth cells are over-regulated (PCNA, members of the cycling family: CDC20, CDK4, Myb) while other genes of the Wnt catenin-β family and metalloproteinases were modulated in the expression of HCC [37Park C-Y, Choi S-H, Kang S-M, et al. Nonstructural 5A protein activates beta-catenin signaling cascades: implication of hepatitis C virus-induced liver pathogenesis. J Hepatol 2009; 51(5): 853-64.[http://dx.doi.org/10.1016/j.jhep.2009.06.026] [PMID: 19726098] ].

The expression of miRNAs in hepatic tissue is related to the pathogenesis of liver disease, including, hepatocellular carcinoma. Different mi-RNA are downregulated in HCC and need more studies to evaluate the real role of this RNA [38Dhayat SA, Hüsing A, Senninger N, et al. Circulating microRNA-200 family as diagnostic marker in hepatocellular carcinoma. PLoS One 2015; 10(10) :e0140066-40Wen Y, Han J, Chen J, et al. Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma. Int J Cancer 2015; 137(7): 1679-90.[http://dx.doi.org/10.1002/ijc.29544] [PMID: 25845839] ]. These and other papers indicate that miRNAs may be biomarkers for the evaluation of HCC, but candidate miRNAs are different. Further research is definitely required in future works.

5. HCV AND HCC: ANY RELATIONSHIP WITH DAAS?

The advent of novel direct-acting antivirals (DAAs) has totally changed the landscape of HCV therapy. In fact, HCV infection cure rate is estimated at around 90%, with a sustained virological response (SVR) of around 95-97% [41Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and sofosbuvir plus ribavirin for treatment of HCV infection in patients with advanced liver disease. Gastroenterology 2015; 149(3): 649-59.[http://dx.doi.org/10.1053/j.gastro.2015.05.010] [PMID: 25985734] , 42Poordad F, Schiff ER, Vierling JM, et al. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology 2016; 63(5): 1493-505.[http://dx.doi.org/10.1002/hep.28446] [PMID: 26754432] ]. These results have raised the hope of an improvement in disease severity. One of the main expectations following DAA treatment is not only to eradicate the virus, but to improve liver function too, such as cirrhosis, fibrosis and HCC. In particular, the reduction of inflammation can lead to a decrease of cirrhosis and HCC.

Indeed, in the past, Interferon (IFN) based therapies have demonstrated that this treatment resulted in an increased HCV clearance and that SVR had reduced liver fibrosis, cirrhosis and HCC [43Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122(5): 1303-13.[http://dx.doi.org/10.1053/gast.2002.33023] [PMID: 11984517] , 44Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005; 142(2): 105-14.[http://dx.doi.org/10.7326/0003-4819-142-2-200501180-00009] [PMID: 15657158] ]. These data are even more consistent considering the anti-tumor and anti-proliferative effects of IFN [45Lok AS, Everhart JE, Wright EC, et al. Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C Gastroenterology 2011.]. Nevertheless, given the adverse effects of IFN and ribavirin, a new class of direct-acting antivirals drugs has been introduced. DAAs are antiviral drugs that impact HCV replication at different stages, such as protein assembly or polymerase activity.

But what’s the real effect of DAAs on HCC in HCV populations? Not much data on the role of DAAs-induced HCV eradication in HCC occurrence are available. Recently, some controversial data have been published on the relationship between HCC recurrence and DAAs treatment in HCV spanish population. In fact, Reig et al show that despite a high rate of SVR after treatment with DAAs, an elevated number of HCC recurrence has been observed in their cohort. In particular, they included 55 HCV patients, with a complete radiological response after a prior history of HCC who received DAAs, as a final study population and they observed a radiologic tumor recurrence of (27.6%) (16 of 55 patients) [46Reig M, Mariño Z, Perelló C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016; 65(4): 719-26.[http://dx.doi.org/10.1016/j.jhep.2016.04.008] [PMID: 27084592] ]. The observed a very close time between DAAs treatment and cancer recurrence (median time 3,5 months). In their opinion, these data raise a concern about the benefit of DAAs on HCV patients with a prior HCC history.

Another study of Conti et al. found that, during the 24 weeks follow-up evaluation, HCC was detected in 26 of 344 HCV patients (7.6%). In particular, HCC developed in 17 of the 59 patients with a prior history of HCC (28.81%), and in 9 of the 285 (3.2%) who did not expertise cancer in their life [47Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016; 65(4): 727-33.[http://dx.doi.org/10.1016/j.jhep.2016.06.015] [PMID: 27349488] ]. In both these studies a high rate of SVR is observed, confirming real effectiveness of DAAs against HCV infection. When Conti et al. compared these data with HCC recurrence in HCV untreated population, they found a similar rate of cancer development, suggesting that it is not possible to affirm that DAAs treatment is involved in HCC.

Another study by The ANRS collaborative study group on hepatocellular carcinoma, in France, reported that no increased risk of HCC recurrence in HCV populations has been observed following DAAs treatment [48Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts. J Hepatol 2016; 65(4): 734-40.[http://dx.doi.org/10.1016/j.jhep.2016.05.045] [PMID: 27288051] ].

Furthermore, the HCC recurrence found by Conti et al. is similar to that found in an Italian study in which the authors indicate that HCC recurrence after 1 year from the surgical resection of the tumor is around 20% [49Pompili M, Saviano A, de Matthaeis N, et al. Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤3 cm. Results of a multicenter Italian survey. J Hepatol 2013; 59(1): 89-97.[http://dx.doi.org/10.1016/j.jhep.2013.03.009] [PMID: 23523578] ].

One of the most important concerns is to understand why a sudden HCC recurrence after DAAs treatment is observed.

An explanation of these results is not yet reached but one of the main hypotheses is that following DAAs treatment a perturbation of the immune system occurs.

In fact, it’s been hypothesized that changes in pro and anti-tumor signals after DAAs treatment could impact on the HCC recurrence. For example, DAAs therapy-induced SVR could cause the reduction of Natural Killer (NK) cells and their role in immuno surveillance, enhancing the growth of the undetected tumor [50Serti E, Park H, Keane M, et al. Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNα. Gut 2017; 66(4): 724-35.[http://dx.doi.org/10.1136/gutjnl-2015-310033] [PMID: 26733671] ]. This phenomenon is unlikely in HCV patients treated with IFN, because of the immuno modulatory and anti-proliferative effect of this cytokine [51Nault J-C, Colombo M. Hepatocellular carcinoma and direct acting antiviral treatments: Controversy after the revolution. J Hepatol 2016; 65(4): 663-5.[http://dx.doi.org/10.1016/j.jhep.2016.07.004] [PMID: 27417216] ].

Consistent with this hypothesis, an Italian study speculated that drugs could induce HCC recurrence through an increase in tumor cells dissemination. In particular, Villani et al. found an increase in vascular endothelial growth factor (VEGF) levels during DAAs therapy, while they normalized within 12 weeks at the end of therapy [52Villani R, Facciorusso A, Bellanti F, Tamborra R, Piscazzi A, Landriscina M, et al. 2016.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172554/]. The serum of these patients, also, had angiogenic properties, when tested in an in vitro cells stimulation assay [52Villani R, Facciorusso A, Bellanti F, Tamborra R, Piscazzi A, Landriscina M, et al. 2016.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172554/]. VEGF is a critical factor in angiogenesis, that is mainly responsible for tumor dissemination and it seems to correlate with a rapid development and recurrence of HCC [53Zhu AX, Duda DG, Sahani DV, Jain RK. HCC and angiogenesis: Possible targets and future directions. Nat Rev Clin Oncol 2011; 8(5): 292-301.[http://dx.doi.org/10.1038/nrclinonc.2011.30] [PMID: 21386818] ]. The effects of DAAs on inflammatory pattern and on the immune system seem to be related to the onset of HCC in HCV population. Other studies reported changes in the immune system and the reduction of IFN producing cells following DAAs treatment [50Serti E, Park H, Keane M, et al. Rapid decrease in hepatitis C viremia by direct acting antivirals improves the natural killer cell response to IFNα. Gut 2017; 66(4): 724-35.[http://dx.doi.org/10.1136/gutjnl-2015-310033] [PMID: 26733671] , 54Meissner EG, Wu D, Osinusi A, et al. Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome. J Clin Invest 2014; 124(8): 3352-63.[http://dx.doi.org/10.1172/JCI75938] [PMID: 24983321] ], suggesting that DAAs can reset HCV viral load but could be involved in modifying the inflammatory pattern and the immuno surveillance against HCC.

6. DAA-RAMS OCCURRENCE AND HCC DEVELOPMENT

An important issue to face is the onset of DAAs related- resistance associated mutations (RAMs). Treatment with DAAs that target the HCV protease NS3/4A, NS5A and the NS5B polymerase proteins can lead to more than 90% SVR [55Gozlan Y, Mendelson E, Ben-Ari Z, Mor O. Resistance of hcv to new direct acting antivirals. Harefuah 2015; 154(11): 684-687, 743.[PMID: 26821497] ].

HCV has higher diversity and variability in its genome compared to other viruses. During its replicative cycle, a lot of mutations occurs in the genome, creating a pool of virus variants termed “quasispecies” [56Ahmed A, Felmlee DJ. Mechanisms of hepatitis c viral resistance to direct acting antivirals. Viruses 2015; 7(12): 6716-29.[http://dx.doi.org/10.3390/v7122968] [PMID: 26694454] ].

RAMs are often used to describe the amino acid substitutions that reduce the susceptibility of a virus to a drug.

Viral resistance after DAAs administrations occurs when some viral variants with reduced susceptibility to drugs are selected and replicate [57Bartenschlager R, Lohmann V. Replication of hepatitis C virus. J Gen Virol 2000; 81(Pt 7): 1631-48.[http://dx.doi.org/10.1099/0022-1317-81-7-1631] [PMID: 10859368] ]. Resistance of HCV to DAAs is determined by many factors such as the genetic factors, related to the number and type of nucleotide substitutions and the number of mutations required for a virus to acquire full resistance to the drug [56Ahmed A, Felmlee DJ. Mechanisms of hepatitis c viral resistance to direct acting antivirals. Viruses 2015; 7(12): 6716-29.[http://dx.doi.org/10.3390/v7122968] [PMID: 26694454] ]. Another factor involved in the resistance to DAAs is determined by the fitness of resistant virus populations, which is independent of the level of resistance conferred by RAMs [58Pawlotsky J-M, Hepatitis C. Hepatitis c virus resistance to direct-acting antiviral drugs in Interferon-free regimens. Gastroenterology 2016; 151(1): 70-86.[http://dx.doi.org/10.1053/j.gastro.2016.04.003] [PMID: 27080301] ].

Once resistance is acquired, a high risk of treatment failure occurs.

Sometimes, in patients with suboptimal response to treatment, HCV variants with a different level of susceptibility may exist naturally at low levels in the absence of drug, promoting resistance to direct acting antiviral agents and treatment failure [59Kieffer TL, Kwong AD, Picchio GR. Viral resistance to specifically targeted antiviral therapies for hepatitis C (STAT-Cs). J Antimicrob Chemother 2010; 65(2): 202-12.[http://dx.doi.org/10.1093/jac/dkp388] [PMID: 19903720] ].

Relapse of HCV in patients who initially respond to DAA may be due to the replication of a residual variant that remained below the limit of detection at the end of treatment. After relapse, viral sequencing may identify the virus sequence present after treatment, but sometimes an important phenomenon could occur after relapse; in fact it is possible that a viral population could evolve to wild type prior to sequencing after relapse, as it is not under selective pressure at the time [56Ahmed A, Felmlee DJ. Mechanisms of hepatitis c viral resistance to direct acting antivirals. Viruses 2015; 7(12): 6716-29.[http://dx.doi.org/10.3390/v7122968] [PMID: 26694454] ].

The viral variants following a treatment failure are resistant to one or several of the drugs administered [56Ahmed A, Felmlee DJ. Mechanisms of hepatitis c viral resistance to direct acting antivirals. Viruses 2015; 7(12): 6716-29.[http://dx.doi.org/10.3390/v7122968] [PMID: 26694454] ].

In these not rare cases the viral trigger is even more difficult to suppress and it could play a pivotal role in the onset of HCC. Indeed HCC risk was increased 17-fold in HCV-infected patients compared with HCV-negative controls and in many of these cases, HCC patients might have had HCV detected by polymerase chain reaction testing of liver tissue and/or serum, even if antibody to HCV (anti-HCV) was nondetectable [5de Oliveria Andrade LJ, D’Oliveira A, Melo RC, De Souza EC, Costa Silva CA, Paraná R. Association between hepatitis C and hepatocellular carcinoma. J Glob Infect Dis 2009; 1(1): 33-7.[http://dx.doi.org/10.4103/0974-777X.52979] [PMID: 20300384] ]. A failure or relapse in HCV therapy may have a decisive weight in favoring the development of HCC. To ensure effective treatment the HCV subtype should be determined prior to therapy and resistance testing could be an important weapon to fight all the detrimental effects generated by virus escape and replication, which are the basis of HCC onset in HCV patients.

CONCLUSION

Future studies on this phenomenon should report data from bigger sample size with a longer follow-up period. Moreover, the distinct clinical characteristics of the patients, included in the studies should be uniform. For example, Villani et al. show that Reig et al. recruited some patients who were treated with “non-curative” practice, such as chemoembolization, characterized by early recurrence tumor rates. This could explain the high rate of HCC recurrence observed by the Spanish group [52Villani R, Facciorusso A, Bellanti F, Tamborra R, Piscazzi A, Landriscina M, et al. 2016.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172554/].

All these results show that, in particular for those patients who experienced HCC, all patients should be followed, both during and after DAAs therapy.

In conclusion, all data available do not seem to directly correlate DAAs therapy with HCC development in HCV treated patients, although patients who experienced HCC showed a high rate of tumor recurrence.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

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(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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